EDITORIAL COMMENT Hair abnormalities range from uncommon genetic conditions to some of the most common diseases we see in our clinics. Maria Hordinsky is an expert in all of them. In this comprehensive well-written review the latest information is concisely presented. A simplified classificaton of the inflammatory alopecias is now the accepted standard; treatment is recommended in ranked tiers. This practical advice is welcome. Additionally the advances in our understanding of the hair cycle and structure leads me to have hope for more rational, effective and hopefully safe, alternative therapies for androgenetic alopecia may be closer to reality.
Significant progress in the diagnosis of infantile vascular tumors has been achieved during the past 2 decades because of improvements in the recognition of clinical characteristics, radiologic features, and histopathologic analysis, as well as the discovery of important immunophenotypic markers such as GLUT-1. These recent advances make it possible to define more clearly the distinct clinical entities with their variable prognoses and to improve the management of lesions that, although histologically benign, infrequently may be lethal because of their invasive potential.
Toll-like receptors (TLRs) are important pattern-recognition receptors involved in host defense against a variety of pathogenic microorganisms. Activation of TLRs leads to the production of cytokines, chemokines, antimicrobial peptides, and upregulation costimulatory and adhesion molecules involved in innate and adaptive immune responses. TLRs are expressed on a variety of cell types found in the skin, including keratinocytes and Langerhans cells in the epidermis, resident and trafficking immunesystem cells such as macrophages, dendritic cells, T and B cells, and mast cells in the dermis, endothelial cells of the skin microvasculature, and skin stromal cells such as fibroblasts and adipocytes. There have been an increasing number of reports demonstrating that TLRs play a key role in cutaneous host defense mechanisms against bacterial, fungal, and viral pathogens. In addition, TLRs have also been implicated in the pathophysiology of various inflammatory skin diseases.
Surgery on the nose is inseparable from the practice of dermatology. Extensive training and experience is required to account for the nose's unique role in determining individuality, its function as an airway, and its predilection for hosting aggressive tumors. This overview of anatomy and general surgical principles provides the novice with a foundation on which to build and the experienced practitioner a review of pertinent literature.
Cutaneous SCC is the second most common skin cancer among whites. Most cases of primary cutaneous SCC are induced by UV radiation. Chronic sun exposure is the major risk factor, and favored locations include the head and neck and other sun-exposed areas. Moreover, it is important for the clinician to recognize other risk factors associated with this malignancy, including HPV infection, occupational exposures, various genodermatoses, scarring dermatoses, chronic wounds, and burn scars. The allogenic transplant population is at most risk for developing cutaneous SCC. For these patients, aggressive patient education, control of immunosuppression, and clinical surveillance should be the standard of care. Most patients who have primary SCC have an excellent prognosis, and treatment is usually straightforward. A substantial minority of these neoplasms, however, may recur or metastasize. Obtaining a complete history and performing a total-body skin examination can help to identify tumors at high risk for recurrence or metastasis in addition to those that may be more easily treated. For those individuals with metastatic disease, however, the long-term prognosis is guarded. Based on recent reports, in the future, there may be a role in SLNB for cutaneous SCC to diagnose subclinical metastasis accurately. Larger studies and better guidelines need to be developed before SLNB can be routinely used in the management of metastatic disease. Physicians should emphasize to their patients the benefits of sun avoidance and protection from sunlight, beginning in childhood, to minimize the risk for developing this potentially life-threatening neoplasm.
Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed interest in the effect of dietary interventions on acne, the elucidation of the involvement of TLR and MMPs in acne pathogenesis, and a more detailed functional understanding of various treatment modalities at the molecular level are all promising indications that advances in therapeutics are sure to follow. Health utilities will serve not only as powerful outcome measures of treatment effects but also as clinical decision-making aids in everyday practice. It is hoped that future advances will further uncover additional molecular and cellular details of pathophysiology, leading to rational targeted design of medications, and advance clinical management through improved understanding of the psychosocial impact of acne on patients.
Physicians have long been intrigued by the distinct patterns created by epidermal nevi and other mosaic cutaneous disorders. Although many of the molecular mechanisms underlying these disorders remain unrevealed, with the release of the results of the Human Genome Project our knowledge is rapidly increasing. The underlying genetic defects for many of the X-linked and mosaic disorders have recently been identified. Advances in technology, such as the array comparative genomic hybridization, will provide the tools for continued gene discovery and expanded understanding of the pathogenic mechanisms underlying mosaic skin conditions.
Dimethyl fumarate (DMF) is a fumaric acid ester that is used to treat psoriasis and multiple sclerosis. Recently, DMF was found to exhibit anti-tumor effects. However, the molecular mechanisms underlying these effects have not been elucidated. In this study, we investigated the mechanism of DMF-induced apoptosis in different human hematopoietic tumor cell lines. We found that DMF induced apoptosis in different human hematopoietic tumor cell lines but it did not affect the normal human B lymphocyte cell line RPMI 1788. We also observed a concurrent increase in caspase-3 activity and in the number of Annexin-V-positive cells. Furthermore, an examination of the survival signals, which are activated by apoptotic stimuli, revealed that DMF significantly inhibited nuclear factor-κB (NF-κB) p65 nuclear translocation. In addition, DMF suppressed B-cell lymphoma extra-large (Bcl-xL) and X-linked inhibitor of apoptosis (XIAP) expression whereas Bcl-2, survivin, Bcl-2-associated X protein (Bax), and Bim levels did not change. These results indicated that DMF induced apoptosis by suppressing NF-κB activation, and Bcl-xL and XIAP expression. These findings suggested that DMF might have potential as an anticancer agent that could be used in combination therapy with other anticancer drugs for the treatment of human hematopoietic tumors.
Tumorigenesis is traditionally thought to be caused by the imbalance between oncogenes and tumor-suppressor genes. Epigenetics is a recently described phenomenon that uses an alternative mechanism to explain the transcriptional inactivation of tumor-suppressor genes predominantly by hypermethylation of the promoter regions. Hypermethylation of these regions has been described extensively in many neoplasms, including cutaneous melanoma. Histone modification, primarily by acetylation and deacetylation, is a current potential target for melanoma therapy, but more research is required to understand the mechanisms involved and the therapeutic effectiveness of regimens involving these agents. These mechanisms not only are important for understanding the origin and progression of neoplasms but also have important potential therapeutic implications. Understanding the epigenetic mechanisms involved in melanoma can provide valuable information with significant implications in diagnosis, treatment, and prevention.
Psoriasis represents a potentially life-altering disease that can profoundly impact physical, emotional and social functioning, and overall quality of life. The majority of cases are mild and managed adequately with topical medications. A minor subset of children present with severe, rapidly evolving disease that requires systemic therapy. The choice of treatment in children, as in adults, is determined by disease acuity, morphology, distribution, severity and the presence of comorbidities such as psoriatic arthropathy. Practical considerations such as ease of use, patient acceptability, accessibility, risk to benefit ratio, cost and individual perceptions of disease and quality of life are factored into treatment decisions. Part I of this 2-part series will focus on topical agents, their varying degrees of effectiveness, potential side-effects and applications in clinical practice.
Recent epidemiological observations reveal that the prevalence of psoriasis increases more rapidly in young women compared with young men, and that the prevalence of psoriasis may decrease in the elderly. Emerging evidence suggests that some potentially modifiable exposures, such as smoking, stress and obesity, may increase a patient's risk of developing psoriasis. The evolving literature suggests that psoriasis is associated with multiple other diseases, including cancer, cardiovascular disease, diabetes and psychiatric disease, and that psoriasis itself may be an independent risk factor for developing atherosclerosis and myocardial infarction. The treatment of moderate-to-severe psoriasis is undergoing a revolution with the advent of biological therapies that target the immunopathogenesis of psoriasis, such as tumor necrosis factor-alpha and T-cell function. The pharmacokinetics, pharmacodynamics, efficacy and safety profiles vary among biologicals and, therefore, drug and patient factors are important in selecting the optimum therapy. In this article, we focus on recent developments in the epidemiology and systemic treatment of psoriasis.
The damaging impact of cutaneous melanoma on individuals and society is apparent. As dermatologists, we are in a unique position to help each patient on a personal level and make contributions with sweeping effects on a societal level. On an individual level, the successful care of each patient involves accurate and early diagnosis, proper education, sufficient biopsy, adequate surgical and medical managements, and long-term follow-up. It is also imperative to remember that each patient presents with his or her own set of unique challenges and needs. The general assessment of risk factors and predictions on survival outcome should only serve as a starting point for discussion during the consultation. A significant percentage of patients will defy these predictions. On a public health level, the concerted endeavor until now to reduce the incidence of the disease should be viewed as a partial success, considering the recent trends in the incidence and mortality rate of the disease. However, there are still many questions that need to be addressed before the implementation of more comprehensive and effective strategies to control MM mortality. It is only through this unrelenting pursuit by the medical and scientific community that may eventually lead to understanding, and perhaps a cure for, this deadly skin cancer that is easily visualized but has thus far proven difficult to control.
As the age of viability of premature neonates continues to decline, early recognition of emerging cutaneous infections will become increasingly important. Fungal and bacterial infections should always be included in the differential diagnosis of unusual-appearing skin lesions in the premature neonate since prompt evaluation and aggressive therapy is paramount in this high-risk population.
The approach to the patient with genetic immunodeficiency is multidisciplinary, and requires close interaction between the primary care physician, immunologist, and other specialists. Dermatologists may play a key role in both the diagnosis of immunodeficiency based on recurrent infection or specific cutaneous abnormalities and in the management of cutaneous complications. The availability of bone marrow and stem cell transplantation has been life-saving for many affected children. The underlying genetic basis is now known for most forms of immunodeficiency, which has facilitated confirmation of patient diagnosis and prenatal diagnosis. Gene therapy has already been initiated for severe combined immunodeficiency, and will certainly play a growing role in therapy of this group of disorders in the future.
There has been a considerable progress in the understanding of the physiopathology of BP during the past 2 decades. The insights into the humoral and cellular immune response against BP180 and BP230 have increased significantly. Nevertheless, the factors underlying the initiation of the disease leading to a disruption of self-tolerance remain unclear. Clinically, the disease shows protean presentations, and diagnostic delay is common. A practical, relevant, and unresolved question is how to identify patients suffering from BP at an early stage of the disease, when direct immunofluorescence microscopy findings still may be negative. The characterization of markers allowing the differentiation of BP from other pruritic eruptions occurring in the elderly population would be extremely helpful in daily practice. Finally, despite the knowledge that potent topical steroids are efficient in controlling the disease, management of BP sometimes remains difficult and requires systemic therapies. It is hoped that a better knowledge of the regulation of the autoimmune response in BP also will facilitate the design of novel immunomodulatory therapeutic approaches devoid of the severe side effects of current immunosuppressive treatments.
DCs are a complex cell population in the skin consisting of epidermal LCs and dermal DCs, which differ in their anatomic location, antigen recognition, processing machinery, and migratory capacity. Cutaneous DCs (LCs as well as dermal DCs) function as sentinels that survey invading agents and transmit the information into immune responses by taking up exogenous antigens, migrating to draining LNs, and presenting the processed antigens to T cells resulting in T-cell differentiation and activation. Indeed, further studies are needed to clarify the specific contribution of each cutaneous DC subpopulation to antigen presentation and induction of cutaneous immune responses. Recent results suggested to revisit the "paradigm" that exclusively immigrant LCs present skin-acquired antigens to T cells upon reaching the draining LNs, because viral antigens, for instance, are presented by a DC subpopulation other than LCs after infection of mouse epidermis with herpes simplex virus [153]. Additionally, different DC subpopulations may sequentially present skin-acquired antigens, possibly serving as a regulatory mechanism of cell-mediated immunity and adding further complexity to established concepts. Nevertheless, cutaneous DCs are involved in several pathologies (including infections, inflammatory disorders, or skin cancers) and play a pivotal role in regulating the balance between immunity and peripheral tolerance. However, it is widely accepted that (cutaneous) DC in an immature state may have tolerogenic properties resulting in the induction or expansion of Tregs. CD4+CD25+ Tregs are essential for the control of immune responses in inflammatory, autoimmune, or cancer diseases, and it is well established that in particular the lineage-specific transcription factor Foxp3, as well as cytokines (including IL-2, IL-10, and TGF-beta), characteristic surface markers such as CTLA-4, and members of the TNF superfamily (e.g., RANKL) are critically involved in the thymic development, peripheral maintenance, and suppressive activity of CD4+CD25+ Tregs. Recently, new methods for generating and expanding Tregs in vitro have emerged and supported the use of CD4+CD25+ T cells as a novel strategy for the treatment of patients suffering from autoimmune diseases. In the future, a better understanding of Treg function in vivo and the interactions of Tregs and pathogenic effector T cells in autoimmune disorders may help to improve the design of Treg-based therapies.
All dermatologists worldwide should have at least passing familiarity with various tropical maladies that generate cutaneous manifestions. In addition to the standard infectious ailments associated with tropical environs, the authors have described herein five "emerging" illnesses that are gaining increasing attention for their capacity to cause human disease in those immigrating from, or traveling to, the tropical and subtropical world.
NSF is a new and emerging disease. Significant investigative work to date has led to an unexpected suspect-gadolinium-containing contrast agents. Considerable additional work is now underway to formulate specific recommendations about the use of these agents in the population of patients who have renal disease. Goals on the immediate research horizon include (1) the identification of risk factors and conditions that must be met to permit the development of NSF in patients who have renal disease, (2) the characteristics of contrast agents that make them more or less likely to induce NSF, and (3) the development of prophylactic or treatment strategies that can reduce the overall development and severity of NSF. The investigative process has already yielded new insight into the functions (and malfunctions) of the CF in the setting of NSF. As the CF is being increasingly implicated in other organ-specific and systemic fibrosing disorders, we can expect to see significant developments in the studies of allied disorders as well.
